Medical Containers with Terephthalate Plasticizer for Storing Red Blood Cell Products

ABSTRACT

Containers for the storage of red blood cell compositions are disclosed. The container walls are made of a plastic composition that includes a polymeric material and at least one extractable agent that includes a terephthalate ester in an amount effective to suppress hemolysis in red blood cells.

BACKGROUND

Red blood cells are often separated from whole blood and collected forlater transfusion to a patient in need of red blood cells. For example,red blood cells (hereinafter “RBCs”) may be administered to a patientsuffering from a loss of blood due to trauma, as a post-chemotherapytreatment, or as part of a treatment of one or more blood bornediseases, such as certain anemias and the like. Unless administeredimmediately after collection from a donor, RBCs must typically be storedfor some period of time prior to transfusion. The storage period may beanywhere from a few days to several weeks.

Prolonged storage of RBCs can (negatively) affect RBC function. In orderfor the RBCs to be suitable for transfusion to the recipient, RBCs mustmaintain adequate cell function and metabolism. For example, RBCs mustmaintain an adequate concentration of adenosine triphosphate (ATP) and2,3-DPG. In addition, the presence of lactate must not be too high inthe stored RBCs. Still further, stored RBCs must have acceptably lowlevels of hemolysis. Typically, an acceptable level of hemolysis isbelow 1.0% (in, for example, the U.S.) and 0.8% (in Europe) after 42 daystorage.

During storage, concentrated RBCs and the additive solutions in whichthey are stored are typically kept in a sealed container, usually madeof a plastic material. Most typically, the containers approved for thecollection of whole blood and the storage of RBCs are made of apolyvinyl chloride (PVC). Inasmuch as polyvinyl chloride can be somewhatrigid or brittle, a plasticizer is typically incorporated into the PVC.One example of a currently known and used plasticizer for medical gradePVC is di-ethylhexyl phthalate ester or DEHP. Other plasticizers thathave been used with PVC or other polyolefin materials include TEHTM, andthe family of citrate esters described in U.S. Pat. No. 5,026,347, thecontents of which is also incorporated by reference herein. In addition,epoxidized oil is often added as a secondary plasticizer to one or moreof the plasticizers described above.

As reported in U.S. Pat. No. 5,026,347 and other literature, such asRock, et al. “Incorporation of plasticizer into red cells duringstorage,” Transfusion, 1984; Horowitz et al. “Stablization of RBCs bythe Plasticizer, Di(ethylhexyl)phthalate,” Vox Sarquinis, 1985, certainplasticizers may have a beneficial effect on the storage life of RBCs.More particularly, plasticizers such as DEHP and the family of citrateesters have been found to suppress hemolysis of RBCs stored incontainers that include such leachable plasticizers. InternationalPatent Application No. PCT/US2012/056100, filed Sep. 19, 2012 andincorporated by reference herein in its entirety, discloses plasticcontainers plasticized with 1,2-cyclohexanedicarboxylic acid diisononylester (or DINCH) for the storage of red blood cells with acceptablehemolysis levels.

While DEHP plasticized containers have worked well for the storage ofred cells, the use of other container materials that assist in providinga suitable storage environment for red blood cells remains a topic ofkeen interest. Thus, it would be desirable to provide a container forRBCs wherein the container is at least substantially free of anyleachable phthalate plasticizer but an extractable agent such as aplasticizer that is effective in suppressing hemolysis in red bloodcells. Also, as used herein, the term “extractable agent” includesextractable plasticizers but also may include agents that act asplasticizers for some materials (e.g., PVC), but do not necessarily actas plasticizers relative to other materials.

SUMMARY

In one aspect, the present disclosure is directed to a biocompatiblecontainer for storing red blood cells and red blood cell products. Thecontainer includes one or more container walls defining an interiorchamber. The container wall(s) is made of a composition that includes apolymeric material and at least one extractable agent that is orincludes a terephthalate ester in an amount effective to suppresshemolysis in red blood cells.

In another aspect, the present disclosure is directed to a red bloodcell product that includes a container having one or more containerwall(s) defining an interior chamber. The container wall is made of acomposition that includes a polymeric material and at least oneextractable agent that is or includes a terephthalate ester in an amounteffective to suppress hemolysis in red blood cells. A suspension of redblood cells is contained within the interior chamber and includesconcentrated red blood cells and an additive solution that includes anutrient and a buffer.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a plan view of a typical RBC storage container used forstoring the RBC suspensions and/or compositions described herein; and

FIG. 2 is a side view of the container of FIG. 1.

DETAILED DESCRIPTION

Disclosed herein are containers for holding red blood cells (RBC) andred blood cell products during a period of storage wherein the containeris made of a plastic material including at least one extractable agentsuch as a plasticizer which is capable of suppressing hemolysis in thestored RBC. More particularly, the container typically is made of aplastic material such as, but not limited to, polyvinyl chloride and atleast one extractable agent that is or includes a terephthalate ester.The RBC product includes concentrated RBCs that have typically beencombined with an additive solution selected to maintain cell functionand metabolism of the RBCs during prolonged storage (e.g., at leastabout 42 days and possibly even up to at least 49 and/or 56 days). Thered blood cells or RBC product is intended for transfusion to a patient.

RBC products include RBC concentrate and an additive solution.Concentrated RBCs are derived from whole blood either by manual orautomated separation collection techniques which will be known to thoseskilled in the art. RBC concentrates may include some residual amount ofplasma. In one embodiment, the RBC concentrate may have most of itsplasma removed as described, for example, in International ApplicationPublication WO/2011/049709, incorporated herein by reference.

As indicated above, the RBC and RBC products described herein may beprovided in a container that is suitable for the long term storage ofRBCs. Preferably, containers for storing the RBC compositions disclosedherein are made of a polymeric material. The containers may be permeableto oxygen or at least semi-permeable to oxygen. As shown in FIGS. 1 and2, container 10 may include one or more container walls 12 which definean interior chamber 15 for receiving the RBC composition 20. In oneembodiment, two sheets made of a polymeric material are brought togetherand sealed along their peripheries 14 by, for example, heat sealing(e.g., RF) to form container 10. Other ways of making container 10 willbe known to those of skill in the art and are within the scope of thepresent disclosure.

As shown in FIG. 2, container wall 12 includes an outer surface 17 andan inner surface 13 which contacts the RBCs stored in the container. Inone embodiment, container wall 12 may be made of a multiple sheetlaminate wherein inner surface 13 is made of one material and outersurface 17 is made of a different material. In either embodiment,container 10 may include one or more access ports 16 for connection withtubing 22, docking devices and the like to establish flow into and outfrom the interior chamber 15 of container 10.

In another embodiment, containers useful in the storage of RBCs asdescribed herein include container walls that are single sheets made inwhole or at least in part of a material that includes at least one ormore polymeric compounds and at least one extractable agent that is orincludes a terephthalate ester in an amount effective to suppresshemolysis in RBCs and still maintain the structural integrity andbiocompatibility of container 12 during manufacture, sterilization anduse. The polymeric material may be blended together with theterephthalate ester and formed into flat sheets that are sealed togetherin the manner described above.

By way of example only, and not limitation, containers of the typedescribed herein may have a container sheet (wall) thickness of betweenapproximately 0.010 to 0.018 inches. They may include a non-smooth orany surface finish that minimizes sheet sticking. Typically, containersof the type described herein may have a container volume (i.e., interiorchamber volume) of approximately 150 ml to 4 L. The containers of thepresent disclosure are preferably sterilized by autoclaving and suchautoclavable containers may typically have a 70-85 durometer (Shore A).

The polymeric material may be preferably made from or otherwise includepolyvinyl chloride. In an alternative embodiment, the polymeric materialmay be one or more non-PVC polyolefin homopolymers, co-polymers orblends thereof. Examples of suitable non-PVC polyolefins includepolypropylene, polyethylene, including ultra low density polyethylene(ULDPE) and very low density polyethylene (VLDPE). Other suitablecompounds that may be used in the plastic materials of the containers oras part of the blend for making the plastic materials include ethylenevinylacetate (EVA) and block co-polymers such as Kraton. Exemplaryformulations and/or polyolefins, polyolefin blends or other polymericcompounds which are useful, either alone or in combination, in themanufacture of containers suitable for use in the RBC products of thepresent disclosure are described in U.S. Pat. No. 5,026,347, 4,140,162,5,849,843, and 6,579,583, all of which are incorporated herein byreference in their entireties. Of course, it will be appreciated thateven in containers where the walls 12 are made without any PVC, some PVCmay be present in a small amounts in the container as a whole, as ports16 may often include plasticized PVC.

Containers for the storage of red blood cells in accordance with thepresent disclosure include at least one extractable agent that is orincludes a paraphthalate ester. In a preferred embodiment, theparaphthalate ester is terephthalate ester. In an even more preferredembodiment, the terephthalate ester is di-2-ethyl hexyl terephthalate(DENT or DOHT). DENT is available from Eastman Chemical Co. ofKingsport, Tenn. under the product name Eastman 168.

Thus, a preferred composition of the present disclosure includespolyvinyl chloride and DEHT in an amount effective to suppress hemolysisof red blood cells. In one embodiment, the composition of the presentdisclosure includes approximately 20-45% by weight, terephthalate ester,such as DEHT. In a more specific embodiment, the composition of thepresent disclosure includes approximately 30% of a terephthalate estersuch as DEHT. The remainder of the composition is made up of the basepolymeric material such as, but not limited to, polyvinyl chloride andoptionally stabilizers and lubricants. Thus, in a specific, non-limitingexample, the composition includes approximately 55%-80% polyvinylchloride and approximately 20%-45% terephthalate ester. The compositionmay also include stabilizers and lubricants. An example of a stabilizeris epoxidized oil. In one non-limiting example, compositions describedherein may include greater than 3.0% of epoxidized oil and less thanapproximately 1.0% of a co-stabilizer such as metal stearate.Stabilizers other than epoxidized oil may also be used.

In another embodiment, the composition of the present disclosure mayinclude polyvinyl chloride, one or more extractable agents orplasticizers such as terephthalate ester and be free of or essentiallyfree of phthalate esters or orthophthalate esters. Thus, by way ofexample, compositions of the present disclosure include a polymericmaterial such as PVC and at least two extractable agents orplasticizers, one of which is a terephthalate ester and the other ofwhich is a non-phthalate and non-orthophthalate ester plasticizer (i.e.,is not DEHP). Preferably, such additional non-phthalate esters have amolecular weight of between approximately 350 to 550. More specificexamples of such non-phthalate or non-orthophthalate agents that may besuitable for use in the PVC containers with a terephthalate esterinclude, for example, epoxodized oil, the family of citrate esters, suchas n-butyryl-n-hexyl citrate (BTHC), acetyltri-n-butyl citrate (ATBC),both of which are described in U.S. Pat. No. 5,026,347, and1,2-cyclohexanedicarboxylic acid diisononyl ester, known by its tradename, DINCH. Thus, in accordance with the present disclosure, at leasttwo, preferably non-phthalate, extractable agents/plasticizers may becombined with the base polymeric material (e.g., PVC) in one embodimentof the composition of the present disclosure.

In a further embodiment, the plastic composition of the presentdisclosure may include first and second extractable agents/plasticizers(wherein one of the first or second agents/plasticizers is preferablyDEHT or other terephthalate ester) and at least a further or thirdplasticizer. The further or third agent/plasticizer may likewise be anon-phthalate plasticizer. The third plasticizer may be a plasticizerthat is not readily extractable or is marginally extractable, such asTEHTM or epoxidized oil (which also acts as a stabilizer) or aplasticizer that is more readily extractable, such as the citrate esteracetyltri-n-butyl citrate (ATBC) or DINCH, and is also effective insuppressing hemolysis. Additional agents or plasticizers may further beincluded in the formulation of the containers described herein.

Thus, in accordance with the examples discussed above, compositions ofthe present disclosure may include approximately 55%-80%, by weight, PVCresin and approximately 20%-45%, by weight, of at least one extractableagent that is or includes a terephthalate ester and one or more otherplasticizers (extractable, marginally extractable or readilyextractable) such as BTHC, DINCH, TEHTM, epoxidized oil, and stabilizersand lubricants. Where the composition includes terephthalate and one ormore additional plasticizers, the terephthalate ester may constitute atleast approximately 5% of the total plasticizer content.

The containers described herein may be used in the storage of red bloodcell compositions. Such compositions may be concentrated RBCs orconcentrated RBCs with an additive solution, i.e., an RBC product. Theadditive solutions may be any known additive solution including Adsol(AS-1) available from Fenwal, Inc. More preferably, the additivesolution may be generally hypotonic and typically (but not necessarily)do not include sodium chloride. Such storage solutions also include anutrient, a buffer and other additives such as sodium citrate. Solutionssuitable for use in the storage of RBCs in accordance with the presentdisclosure typically have a pH of about 8.0 or higher and are describedin U.S. Patent Publication Nos. US 2009/0239208 and US 2011/0117647,both of which are also incorporated herein by reference. In a specificembodiment, the additive solutions include between about 1 to 2.2 mM ofadenine; about 20 mM to about 110 mM of mannitol; about 2.2 mM to about40 mM sodium citrate; about 16 mM to about 30 mM sodium phosphatedibasic and about 20 mM to about 140 mM of glucose. The pH of theadditive solution is above about 8.0.

Thus, concentrated RBCs with some or most of the plasma removed arecombined with additive solutions of the type described above to providethe RBC composition. In one embodiment, the RBC composition includesbetween about 80 to 150 ml of the additive solution combined with about180 to 250 ml of the concentrated RBCs. More preferably, the volume ofadditive solution may be about 100-110 ml. The compositions of thecontainer wall (as described herein) that contacts the RBCs and thestorage medium provide the RBCs with a storage environment thatsuppresses and otherwise maintains level hemolysis.

In the collection of RBCs, it is typical to remove leukocytes from, orat least reduce the number of leukocytes in, the RBCs prior to theirstorage and transfusion. RBCs suspended in an additive solution areoften subjected to a leuko-reduction step which commonly includesfiltration of the RBC/additive solution. Thus, in accordance with themethods and systems disclosed herein, RBCs are subjected to a filtrationstep or other treatment whereby leukocytes and/or other undesirableagents or pathogens such as prions are substantially removed (or thepopulations of leukocytes and/or prions are substantially reduced) fromthe RBCs. In one embodiment, concentrated RBCs may be combined with anadditive solution of the type described above and the combinedconcentrated RBC/additive solution composition may be subjected to theleukocyte and/or prion removal (e.g., filtration) step.

While the containers and compositions disclosed herein have beendescribed in connection with various embodiments, it will be apparent tothose skilled in the art that modifications and variations may be madethereto without departing from the spirit and scope of the invention.

1. A medical container for storing red blood cells comprising: one ormore container walls defining an interiorchamber, said container wall(s)are made of a composition comprising one or more polymeric materials and(b) extractable agents comprising a terephthalate ester, a cyclohexanedicarboxylic acid ester and a citrate ester, said agents being presentin an amount effective to suppress hernolysis in red blood cells.
 2. Thecontainer of claim 1 wherein at least said terephthalate ester comprisesdi-2-ethyl hexyl terephthalate.
 3. The container of claim 1 wherein saidpolymeric material comprises polyvinyl chloride.
 4. The container ofclaim 1 wherein said extractable agents comprise between approximately20%-45%, by weight, of said composition.
 5. The container of claim 1wherein said extractable agents comprise approximately 30% by weight ofsaid composition.
 6. The container of claim 1 wherein said compositionis substantially free of phthalates and orthophthalates.
 7. Thecontainer of claim 1 wherein said composition comprises approximately55%-80% polyvinyl chloride, stabilizers and lubricants.
 8. The containerof claim 1 wherein said citrate ester comprises acetyltri-n-butylcitrate (ATBC).
 9. The container of claim 1 wherein said citrate estercomprises -n-butryl-n-hexyl citrate (BTHC).
 10. The container of claim 1wherein said cyclohexane dicarboxylic acid comprises 1,2 cyclohexanedicarboxylic acid diisononyl ester (DINCH).
 11. (canceled)
 12. Thecontainer of claim 1 wherein at least approximately 5% of saidextractable agents comprises said terephthalate ester.
 13. The containerof claim 1 wherein said container is sterilized by autoclaving,
 14. Thecontainer of claim 1 further comprising one or more ports thatprovide(s) a flow path in flow communication with said interior chamber.15. The container of claim 14 wherein said one or more port(s) is/aremade of a material comprising polyvinyl chloride.
 16. A red blood cellproduct comprising: (a) a container comprising one or more wallsdefining an interior chamber wherein at least a portion of the wall(s)is made of a composition comprising one or more polymeric materials andat least a first extractable agent comprising a terephthalate ester, acyclohexane dicarboxylic acid and a citrate ester, in an amount that iseffective to suppress hemolysis in red blood cells; (b) a suspension ofred blood cells contained within said chamber, said suspensioncomprising: (i) concentrated red blood cells; and i) an additivesolution comprising at least a nutrient and a buffer.
 17. The red bloodcell product of claim 16 wherein said polymeric material is polyvinylchloride and the terephthalate ester is di-2-ethyl-hexyl terephthalate.18. The red blood cell product of claim 16 wherein said compositioncomprises 20%-45%, by weight, of said terephthalate ester, cyclohexanedicarboxylic acid and said citrate ester.
 19. The red blood cell productof claim 16 wherein dicarboxylic acid comprises 1,2 cyclohexanedicarboxylic diisononyl ester.
 20. The red blood cell product of claim16 wherein said additive solution is a hypotonic solution having a pH ofat least approximately 8.0.
 21. The red blood cell product of claim 16wherein said citrate ester is selected from the group ofacetyltri-n-butyl citrate (ATBC) and n-butryl-n-hexyl citrate (BTHC).